At a Glance

A ß-thalassemia may be coinherited with both sickle trait or homozygous sickle disease and will reduce the amount of ß-globin chain production. The presentation is highly variable, depending on the severity of the ß-thalassemia (from mild dysregulation through to null production and whether it is coinherited with Sickle Cell Anemia or with Sickle Trait (see chapters on Sickle Cell Disease and Sickle Cell Trait).

Knowledge of the presence of both the hemoglobin S and ß-thalassemia mutations within a family should raise suspicion for this combination. An elevated percentage of hemoglobin A2 and a mildly elevated hemoglobin F (<5%), together with deviation from the classic pattern of 60% hemoglobin A with 40% hemoglobin S in Sickle trait, are also indicators of this condition. In a term infant, or once the percentage of hemoglobin F declines post-natally, this condition should be identified fairly readily on Newborn Screening programs.

Patients have microcytosis and erythrocytosis and varying degrees of anemia and hemolysis, which are not to be expected with uncomplicated sickle trait. Hemoglobin S trait with a coinherited α-thalassemia should also be considered when the percentage of hemoglobin S is less than 33% (see Chapter Anemia Associated with Hemoglobin S-Alpha Thalassemia). Coinheritance of sickle trait with another ß-chain abnormality, such as C, D, E, or O-Arab, can produce significant sickling disease, and the presentation of these may also be modified by the coinheritance of a ß-thalassemia; these have been described separately (see chapters on Anemia Associated with Hemoglobin S-C, Anemia Associated with Hemoglobin S-D, and Anemia Associated with Hemoglobin O-Arab).

Inheritance of ß-thalassemia with sickle cell anemia reduces the amount of ß-globin produced, and it is immaterial which of the genes carry both mutations. However, the precise nature of the ß-thalassemia can be an important modifying factor. There are several types of ß-thalassemia with differing distribution among ethnic groups.

Beta thalassemias and hemoglobin S have been discussed as discrete clinical entities elsewhere (see chapter on Sickle Cell Anemia). Here, they are considered coinherited mutations.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The tests required for diagnosis and follow-up are identical to those described for hemoglobin S (see chapter on Sickle Cell Anemia).(Table 1)

It is especially important to determine a patient's iron status, since iron deficiency will lower the percentage of hemoglobin A2 produced and could nullify the expected elevation of A2 in beta thalassemia, leading to a missed diagnosis. This is accomplished by demonstrating a reduced serum ferritin (<20 ng/mL) with increased transferrin (or Total Iron Binding Capacity) and a Transferrin Saturation of less than 15%, indicating straightforward iron deficiency. Use of the mean corpuscular volume: red blood cell concentration (MCV/RBC) ratio of less than 14 being indicative of beta-thalassemia, rather than iron deficiency, could prevent this oversight.

If using the value of hemoglobin A2 as a key indicator of β-thalassemia, it is crucial to exclude the presence of Hgb A2'. This delta chain variant is clinically benign but will be present at equal concentration to hemoglobin A2; to obtain an accurate value of delta chain concentrations, hemoglobins A2 and A2' must be added together. It can be difficult to visualize hemoglobin A2' on Electrophoresis or Isoelectric focusing, since the percentage is small and it coelutes with hemoglobin S on high performance liquid chromatography (HPLC).

Glycated hemoglobin S elutes with hemoglobin A2 on HPLC and may falsely elevated the value of hemoglobin A2, leading to erroneous suspicion of β-thalassemia.

Finally, β0-thalassemias may mask the presence of a mutant hemoglobin, since the thalassemia completely suppresses expression of the mutant gene. It is important to ascertain the correct disease state, as this can have significant implications for future generations. If an elevated hemoglobin A2 is not recognized as β-thalassemia, offspring with a partner with benign sickle cell trait could unexpectedly have severe hemoglobin S/Aβ0 disease, rather than benign sickle cell trait.

Additionally, the red cell distribution of hemoglobin F could be determined with the acid elution Kleinhauer-Betke test. Flow cytometry using fluorescently-labeled anti-hemoglobin F is increasingly being used for this purpose. A hetrocellular distribution of hemoglobin F is expected in ß-thalassemias.

Table 1

Coinheritance of Beta Thalassemia with Hemoglobin S Mutations

Classification

Hgb S %

Hgb A %

Hgb A2 %

Hgb F %

Comments

SS (Sickle Cell Anemia)

80-95

0

<3.7

2-20

When F > 15%, see chapters on Anemia Associated with Hemoglobin S-Alpha Thalassemia and Anemia Associated with Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

See chapters on Sickle Cell Anemia and Beta-Thalassemia for effects of hydroxyurea therapy and transfusions.

The incidence of ß-thalassemia in the African population is 1%, and 1 in 13 carry the hemoglobin S mutation. The incidence of trans S-ß-thalassemia is relatively common and occurs at 1 in 625. In this population, the common mutations are in the promoter region upstream to the first exon and results in only a mild decrease in globin chain production (S/Aß+); hemoglobin A is usually 10-15%.

In contrast, a more severe form of S/Aß+, with hemoglobin A at only 1-5%, is seen in Eastern Mediterranean, Iranian, and Indian populations, resulting from splicing mutations in intron 1.

In both of these S/Aß+ classifications, the clinical picture correlates with the percentage of hemoglobin S present.

S/Aß0 is also a common presentation in the Mediterranean, Iranian, and Chinese/Southeastern Asian ethnic groups. This results from a substitution at nucleotide 143 in intron 1 or from nonsense or frameshift mutations in exons 1 or 2. This runs a clinical course similar to Sickle Cell Anemia, but with less hemolysis and a slightly higher hemoglobin concentrations due to the slight decrease in red blood cell (RBC) hemoglobin S concentration. Most of the other complications of Sickle Cell Anemia are the same, except patients commonly have splenomegaly beyond childhood in contrast to autosplenectomy in Sickle Cell Anemia.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

In patients who have different percentages of hemoglobins S, A, and F to those expected in uncomplicated presentations, consideration of alternative hemoglobin variants is important. Even with a β-thalassemia in S trait, there is sufficient hemoglobin present to give a positive sickling test. Other hemoglobins that also give positive sickling tests may need to be considered. With the exception of C-Harlem, most of these are rare or isolated reports. With the exception of Porto-Alegre, all contain the S mutation (ß6 Glu → Val) in addition to the mutation subsequently shown:

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